ABSTRACT Venous access is the most commonly performed invasive medical procedure with over 330 million peripherally inserted venous catheters (PIVC) used annually in the US and 1.2 billion globally. However, the rate of failure prior to completion of therapy remains unacceptably high at 51-90%. Such alarmingly high rate of PIVC failure is primarily attributable to overpenetration through the back wall of the vein resulting in infiltration into the perivascular space. The resulting inflammation or phlebitis as characterized by local pain, redness, blood infiltration and swelling leads to catheter failure and eventual peripheral venous depletion. Current evidence indicates that the presence of phlebitis during the dwell time of the first catheter causes a ~5-fold greater chance of developing phlebitis and failure in subsequent catheters. With 26-54% of first-attempt catheter insertions failing, a strong correlation exists between the successful placement of the first catheter with the onset of phlebitis that stems from initial overpenetration. Hence, reducing the incidence of overpenetration and consequently phlebitis during the first attempt will improve the ability to deliver therapy and minimize patient complications. In recognition of this correlation, specialized IV teams have been implemented which have improved the success rates thus providing strong support to the importance of successful placement of PIVCs on the first-attempt as well as the dependence on operator skill level. The current proposal seeks to address these limitations by establishing the feasibility of a novel PIVC to provide first-attempt, single wall venous access regardless of operator skill level or ability to visualize the vein. The TrueCath system incorporates a mild vacuum in the flashback chamber which upon entering the vein and sensing the change in pressure, safely and quickly deploys the soft gel IV catheter forward via a simple spring mechanism that can easily be incorporated into current PIVC devices. Importantly, the catheter portion is deployed quickly enough to prevent overpenetration that would otherwise occur due to the delay in blood entering the flashback chamber which serves as the index of access and major limitation of current PIVCs. Initial bench and in vivo studies have demonstrated the ability of the TrueCath system to sustain vacuum and release the catheter portion at the appropriate force and speed to provide a 98% first-attempt success rate in vivo. Hence, the system is ready for final refinement which includes modification to the current safety feature and addition of a hemostasis valve within the hub assembly. Performance of the device and additional features will be characterized first on bench (Aim 1) followed by in vivo assessment for reductions in overpenetration, phlebitis and number of attempts (Aim 2). Successful execution of these Phase I studies will appropriately position the TrueCath system for full development, clinical studies and regulatory approval (future Phase II) of a novel and highly innovative approach to resolve PIVC complications and improve the standard of patient care.